Multiple inactivating mutations of the urate oxidase (UOx) gene of humans and apes account for our markedly elevated urate levels compared to all other mammals, and have been hypothesized to confer a selective advantage through urate's potent antioxidant properties. However, in humans the only established effects of high urate levels on health are pathological due to crystal formation in joints (gout) and kidney (stones). Recently, urate has been identified as a robust biomarker of reduced risk and slower progression in Parkinson's disease (PD), suggesting that urate may be neuroprotective and prompting clinical development of urate elevation as a promising neuroprotective strategy in PD. Oxidative damage to mitochondrial DNA (mtDNA) and somatic mtDNA mutations accumulate with age in substantia nigra neurons and may contribute to mitochondrial dysfunction in aging and in neurodegenerative disease like PD. By combining the complementary expertise of a laboratory investigating mitochondrial dysfunction in the CNS with another lab characterizing the neuroprotective potential of purines like urate, the proposed exploratory project will test the central hypothesis that urate plays a crucial role in maintaining mitochondrial integrity. Specific Aim 1 will assess whether disruption of the UOx gene, which elevates urate levels, will reduce the accumulation of somatic mtDNA mutations in the brain in Polg mutator mice expressing a proofreading-deficient mtDNA polymerase gamma (PolgD257A) and will attenuate the characteristic premature aging phenotype (including metabolic and behavioral deficits) of these mice. Conversely, Specific Aim 2 will determine with overexpression of the UOx gene, which lowers urate levels, will enhance the accumulation of somatic mtDNA mutations and in turn exacerbate the premature aging phenotype. The insights gained from the proposed collaborative project will shed light on a virtually unexplored but fundamental aspect of mitochondrial dysfunction in the aging brain, with a potentially high impact on our understanding of basic neurobiology of mitochondrial function, and the potential role of somatic mtDNA mutations. This work also has high relevance to translational neuroscience as well as human evolution. It may form the foundation for exploring the role and therapeutic potential of targeting urate in mitochondrial deficits of PD and other neurodegenerative diseases.